Phosphatidylinositol 3-kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10227350-B2
Application number	US-201715711902-A
Country	US
Kind code	B2
Filing date	Sep 21, 2017
Priority date	Sep 23, 2016
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

The present application provides the compounds of formula I

or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein s, t, n, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein.

First claim

What is claimed:

1. A compound having the structure of formula (I):

wherein n is 1, 2, 3 or 4;
s is 1 or 2;
t is 1 or 2;
each R 1 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 100 ;

R 2 is selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R, —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 101 ;

R 3 is selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 102 ;

R 4 is a 5-10 membered heteroaryl;
wherein said 5-10 membered heteroaryl is optionally substituted with one to four R 103 ;

each R 5 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 104 ;

each R 6 is independently hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
each R a and R b is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, is optionally substituted with one to four R 200 ;

each R 100 , R 101 , R 102 , R 103 and R 104 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R c , —C(O)OR c , —C(O)NR c R d , —N(R c )C(O)R d , —N(R a )C(O)NR a R b , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —NR a S(O) 2 R a , —S(O)NR c R d , —S(O) 2 NR c R d , —S(O)R g , —S(O) 2 R g , —NR c R d , —OR c , —SR d , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 201 ;
each R c and R d is independently selected from hydrogen, C 6-10 aryl, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;

each R 200 and R 201 is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R e , —C(O)OR e , —C(O)NR e R f , —N(R e )C(O)R f , —S(O)NR e R f , —S(O) 2 NR e R f , —S(O)R g , —S(O) 2 R g , —NR e R f , —OR e , —SR e , C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
each R e and R f is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;

each R g is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 200 ;

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

2. The compound of claim 1 having the structure of formula IA:

wherein n, s, t, R 1 , R 2 , R 4 , R 5 and R 6 are as defined in claim 1 ;
X 1 is N or C;
each X 2 , X 3 , X 4 and X 5 is independently selected from S, O, CR 10 and NR 11 ;
wherein each R 10 is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;
wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R 201 ;

wherein each R 11 is independently selected from absent, hydrogen, halo, cyano, hydroxy, amino, —C(O)R a , —C(O)OR b , —C(O)NR a R b , —N(R a )C(O)R b , —S(O)NR a R b , —S(O) 2 NR a R b , —S(O)R g , —S(O) 2 R g , —NR a R b , —OR a , —SR b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S;

or one R 10 and one R 11 group, together with the atoms to which they are attached form a five, six or seven membered fused, or bridged ring;
or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

3. The compound of claim 1 , wherein R 3 is selected from:

wherein t is 1 or 2;
wherein e

Assignees

• Gilead Sciences Inc

Inventors

• Chandrasekhar Jayaraman
• Patel Leena
• Perreault Stephane
• Phillips Gary
• Till Nicholas Alexander
• Treiberg Jennifer Anne

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title